20-hydroxy-21-norcholanic acid gamma-lactones



United States Patent 3,542,773 20-HYDROXY-21-NORCHOLANIC ACID 'y-LACTONES Yvon Lefebvre, Pierrefonds, Quebec, Canada, assignor to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 19, 1968, Ser. No. 753,724 Int. Cl. C07c 173/00 US. Cl. 260-23957 6 Claims ABSTRACT OF THE DISCLOSURE There are disclosed herein 20-hydroxy-2l-norcholanic acid 'y-lactones of the estrane and the androstane series, in particular those in which the steroid nucleus is that of estrone, equilenin, and 70:,8-6POXY6SIIOII6, as well as their 3-alkyl, 3-cycloalkyl, and 3-tetrahydropyrany1 ethers, and their 3-acylates containing from 2-7 carbon atoms in the acyl group. The compounds are gonadotrophin-suppressant agents, and methods for their preparation and use are also disclosed.

The present invention relates to 20-hydroxy-21-norcholanic acid 'y-lactones of the Formula I in which P represents the A, B, and C rings of a steroid nucleus of the estrane or the androstane series with the appropriate substituents attached thereto.

More particularly, a proposed embodiment of this invention relates to 20-hydroxy-21-norcholanic acid 'y-lactones of the Formulae II, III, and IV III in which R represents hydrogen, an alkyl group containing from 1-4 carbon atoms, a cycloalkyl group containing from 5-6 carbon atoms, the tetrahydropyranyl group, or an acyl group containing from 2-7 carbon atoms. This 3,542,773 Patented Nov. 24, 1970 preferred embodiment also relates to the process for preparing the above compounds.

The 20-hydroxy-2l-norcholanic acid 'y-lactones of the preferred embodiment of this invention possess antigonadotrophic activities. More particularly, these lactones exhibit utility as antigonadotrophic agents in standard pharmacological tests, for example, in the test on parabiotic rates (female to female) described by C. Revesz and C. I. Chappel, J. Reprod. Fert., 12, 473 (1966). In this test, the above lactones suppress gonadotrophins without showing estrogenic effects as measured by the increase in uterine weight of the castrated partner.

When the above 20-hydroxy-2l-norcholanic acid -lactones are employed as antigonadotrophic agents in warmblooded animals, for example, rats, they may be administered orally, alone or in tablets combined with pharma cologically acceptable excipients, such as starch, milk sugar and so forth. They may also be administered orally in the form of solutions in suitable vehicles such as vegetable oils.

The dosage of these 20-hydroxy-2l-norcholanic acid -lactones will vary with the particular compound chosen and form of administration. Furthermore, it will vary with the particular host under treatment. Generally, the compounds of this invention are administered at a concentration level that affords the desired pharmacological effect without any deleterious side effects. Those effective concentration levels are usually obtained with a therapeutic range of 0.1 to 50 mg. per kilo per day with a preferred range of 05-20 mg. per kilo per day. In the preferred embodiment of this invention, the starting materials are estrone, equilenin and 7a,8-epoxyestrone and their corresponding 3-alkyl, 3-cycloalkyl or 3-tetrahydropyranyl ethers, as represented by Formula V in which P represents the A, B and C rings of those steroids with the appropriate substituents attached thereto. The alkyl and cycloalkyl ethers are prepared according to the methods described by F. Glockling and D. Kingston, Chemistry and Industry, 1037 (1961) and the tetra'hydropyranyl ethers are prepared according to the method of A. D. Cros et al., Steroids, 4, 423 (1964). 7a,8-Epoxyestrone and its corresponding 3-ethers are readily prepared by treating equilin or the appropriate 3-ether of equilin, prepared by the methods of Glockling and Kingston or Cross et al., cited above, with a peracid preferably m-chloroperbenzoic acid in an inert solvent, preferably chloroform. Estrone, equilin and equilenin are well-known naturally occurring steroids; for example, see L. F. Fieser and M. Fieser, Steroids, Reinhold Publishing Corporation, New York, 1959.

The starting materials described above are treated with Z-furyllithium in a mixture of ether-toluene at room temperature to yield the corresponding 17a-[2'-furyl]-l7;3- hydroxy steroids of Formula VI in which P has the same significance as defined above. During the course of this reaction, it is preferable to protect a free 3-hydroxy group if present; otherwise, a complex is formed between the hydroxy group and the Z-furyllithium, which wastes the furyllithium and adversely affects the yield of the product. Such temporary protection is readily afiorded by tetrahydropyranyl group which may be conveniently removed by subjecting the reaction product to hydrolysis under mildly acidic conditions, for example, dilute hydrochloric acid in methanol. Other suitable methods for protecting a free 3-hydroxyl group are described in Advances in Organic Chemistry, vol. 3, p. 191, New York and London, 1963.

Z-furyllithium is prepared by the action of n-butyllithium upon Z-bromofuran in ether at room temperature. A1- ternatively, 2-furyllithium is also obtained by the action 3 of n-butyllithium upon furan in ether at room temperature. In turn, 2-bromofuran is obtained by decarboxylation of S-bromo-Z-furoic acid by the method of A. F. Shepard et al. (I. Am. Chem. Soc., 52, p. 2083 (1930)).

The above 17u-[2'-furyl]-17/3-hydroxy steroids containing a free phenolic hydroxy group in position 3 prepared as described above, may be preferentially esterified at said position by conventional means with appropriate acid anhydrides or acid halides in pyridine at room temperature, to yield the corresponding 3-acy1 derivatives. These 3-acyl derivatives are useful for preparing the corresponding 3-acyl l7fl-hydroxy-19,21-dinorcholane intermediates of this invention.

The above 17w[2-furyl]-l7B-hydroxy steroids and their 3-acetates and 3-ethers are useful per se as powerful estrogens.

The above l7a-[2' furyl]-17/3-hydroxy steroids are treated with one to two molar equivalents of a hypohalous acid such as, hypobromous or hypochlorous acid or a reagent capable of furnishing the elements of a hypohalous acid upon contact with water. Preferred reagents for this reaction are certain N-haloimides or N-haloamides, such as, N-bromoor N-chlorosuccinimide, or N- chloroor N-bromoacetamide, used with or without small amounts of an acid, preferably perchloric acid; or the reaction may be carried out with an aqueous solution of an alkali metal salt of a hypohalite in contact with acid, such as, for example, sodium hypochlorite and acetic acid. Water must be present and preferred organic solvents include aliphatic and cyclic ethers, such as, for example, diethyl ether, dioxan or tetrahydrofuran; lower aliphatic ketones such as, for example, acetone or methyl ethyl ketone; aromatic hydrocarbons such as, for example, benzene, toluene, or xylene; lower aliphatic esters, such as, for example, the lower alkyl acetates, lower aliphatic carboxylic acids, such as, for example, acetic or butyric acid; lower aliphatic halogenated hydrocarbons such as, for example, chloroform, methylene chloride, or ethylene dichloride; and certain lower aliphatic alcohols such as, for example, methanol and t-butanol. The time of reaction may extend from three minutes to twenty-four hours, and reaction conditions are preferably chosen so as to complete the reaction within one-half hour. The temperature range at which the reactions may be carried out is from -50 C., with temperatures of about 20-30 C. being the preferred range. It might be observed that when N-bromo-succinimide in aqueous methanol at room temperature is being used the oxidation is unusually rapid and is usually complete within five minutes.

Alternatively, the above 17a-[2'-furyl]-17;3 hydroxy steroids are treated with an organic peracid, such as, for example, peracetic acid, perbenzoic acid, monoperphthalic acid, m-chloroperbenzoic acid, and p-nitroperbenzoic acid. The organic peracid utilized may range in amount from approximately 1.1 molar equivalent to 100 molar equivalents, per mole of steroid starting material. Any practical solvent inert to the peracid may be employed. Aliphatic and cyclic ethers, such as, for example, diethyl ether, dioxan, or tetrahydrofuran; lower aliphatic ketones such as, for example, acetone or methyl ethyl ketone; aromatic hydrocarbons such as, for example, benzene, toluene, or xylene; lower aliphatic alcohols, such as, for example, methanol, ethanol, isopropanol, or t-butanol; lower aliphatic acids and their lower alkyl esters such as, for example, acetic acid, ethyl acetate, or butyl acetate; and halogenated hydrocarbons such as, for example, chloroform, methylene chloride, carbon tetrachloride, or ethylene dichloride, are all useful inert solvents. The time of reaction may extend from minutes to 60 hours, with the preferred range being from one-half to twenty-four hours.

In this manner, when starting with the l7u-[2-furyl]- 17B-hydroxy derivatives of estrone, equilenin, or 711,8- epoxy-estrone, the corresponding 17fl-hydroxy-19,2l-dinorcholane derivatives of Formula VII in which P is as defined above, are respectively obtained.

In a variant of the above procedure equilin, its corresponding 3-alkyl or 3-cycloalkyl ethers, or its 3-tetrahydropyranyl ether, described above, are treated with Z-furyllithium in the same manner as described above to yield the corresponding l7a-[2-furyl]-l7fi-hydroxy derivatives of Formula VI in which P represents the A, B, and C rings of equilin together with substituents attached thereto. As noted above, it is desirable to protect a free 3-hydroxy group, if present, with a temporary protecting group such as a tetrahydropyranyl ether during the course of this reaction. Such protective groups may subsequently be removed and be replaced by 3-acyl groups in a conventional manner. Subsequent treatment of the 17u-[2- furyl]-l7/8-hydroxy derivatives of equilin with two equivalents or more of an organic peracid under the conditions described above, affords the compounds of Formula VII in which P represents the A, B, and C rings of 701,8- epoxy-estrone together with the substituents; attached thereto, by simultaneous epoxidation of the 7,8-double bond and oxidation of the 17a-furyl ring.

The compounds of Formula VII in which P represents the A, B, and C rings of estrone, equilin, and 7a,8-epoxy estrone together with the substituents attached thereto may conveniently be referred to as derivatives of 17,8,24-epoxy-19,21-dinorcholane. They are obtained as a mixture of stereoisomeric alcohols due to the introduction of an asymmetric center at position 24. These stereoisomers may be separated by standard chemical procedures, such as crystallization, or the mixture of stereoisomers may be utilized for the preparation of other hydroxy-19,21-dinorcholane derivatives within the scope of this invention. The individual stereoisomers are designated as isomer A and isomer B for convenience. The designation of isomer A, is arbitrarily given to the major stereoisomer which usually constitutes 60-80% of the reaction product.

The individual or mixture of stereoisomers of 1713,24- epoxy-l9,21-dinorcholane derivatives of Formula VII in which P is as defined above are readily oxidized by means of hexavalent chromium, ion to the corresponding ketolactones of Formula VIII, in which P is as defined above. Chromic acid in the presence of sulfuric acid and water, a modification described by A. Bowers et al., J. Chem. Soc., 2548 (1953) is a preferred reagent for this oxidation. During the course of this reaction, if a tetrahydropyranyl group is present at the 3-position of the starting material, said group will be cleaved to the 3-hydroxy group; the 3-tetrahydropyranyl ether may be reformed by subjecting the reaction product to the conditions described by Cross, cited above.

The keto-lactones of Formula VIII obtained as described above may be reduced in the presence of zinc and acetic acid to yield the corresponding keto-lactones of Formula IX and P is as defined above.

Alternatively, the individual or mixture of stereoisomers of the 17,8,24-epoxy-l9-21-dinorcholane derivatives of Formula VII in which P is as defined above may be reduced by hydrogenation in the presence of a noble metal catalyst, such as, for example, palladium, to yield the correspondingly substituted compounds of Formula X and P is as defined above.

The individual or mixture of stereoisomers of the 17,8,24-epoxy-19,2l-dinorcholane derivatives of Formula X and P is as defined above are useful for an alternative preparation of the corresponding keto lactones of Formula IX in which P is as defined above. As such, these norcholane derivatives are oxidized in the same manner as described above to yield the said keto lactones of Formula IX and P is as defined above. These compounds are identical with the same compounds described above.

Finally, the saturated keto-lactones of Formula IX in which P is as defined above are treated with sodium borohydride in solution in a cyclic ether, preferably dioxan, and preferably at a temperature close to room temperature, to yield the corresponding 20-hydroxy-21- norcholanic acid v-lactones of Formula I in which P is as defined above. An'ester group in position 3, if present, will be hydrolyzed in this procedure, to yield the corresponding free phenol, which may, if desired, be re-esterified in the conventional manner.

The following examples and formulae, in which P is as defined above, will illustrate this invention.

EXAMPLE 2 A solution of 2-bromofuran (2.32 g.) in dry ether (46 ml.) is cooled to C. An ethereal solution of n-butyllithium 1.35 N (11 ml.) is added. The mixture is allowed to reach room temperature and is stirred at room temperature for 30 minutes. A solution of estrone 3-methyl ether (2.32 g. in dry toluene (92 ml.) is added and the reaction mixture is stirred at room temperature for 60 hours. Water is added; the organic solvents are washed with water to neutrality, dried and evaporated yielding a yellow gum. The latter product is purified by chromatography on alumina. The fractions eluted with benzene-hexane 1:1 are combined and crystallized several times from hexane to yield the 3-methyl ether of 17a-[2'-furyl]-1,3,5(10)- estratriene-3,17-diol, M.P. 117-119 Alternatively a solution of furan (50 g.), dry ether (1000 ml.) and a 1.53 N ethereal solution of butyllithium (548 ml.) is stirred at room temperature for 1 hour. Then a solution of estrone S-methyl ether (50 g.) in dry toluene (2000 ml.) is added and the mixture is stirred overnight at room temperature. The reaction is worked as above and the residue is chromatographed on basic alumina. The

fractions eluted with mixtures of benzene-hexane and benzene are combined and crystallized from benzenehexane yielding the 3-methyl ether of l7u-[2-furyl]-l,3,5- (10)-estratriene-3,l7-diol, M.P. 124l25.

In the same manner as described above the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl and 3-cyclohexyl ethers of estrone, prepared in Example 1, yield when treated with 2-furyllithium and 3-ethyl, 3- propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl and 3-cyclohexy1 ethers of 17a-[2'-furyl]-1,3,5(10)estratriene-3,17-diol.

EXAMPLE 3 A solution of furan (10 g.) in ether (200 ml.) and a 1.76 N ethereal solution of n-butyllithium (86 ml.) is stirred for one hour at room temperature. Then a solution of equilin 3-methyl ether (10 g.) in toluene (400 ml.) is added and the mixture is stirred for 16 hours at room temperature. Water is added. The organic layer is further washed with water, dried and evaporated to dryness. The residue is chromatographed on basic alumina. The fractions, eluted with benzene-hexane 1:2, are combined, yielding the 3-methyl ether of 17a-[2'-furyl]-1,3,5(10),7- estratetraene-3,17-diol M.P. 116-118 In the same manner, the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl and 3-cyclohexy1 ethers of equilin, described in Example 1, yield respectively the 3-ethyl, 3-propy1, 3-isopropyl, 3-n-butyl, 3-sec.- butyl, 3-cyclopenty1 and 3-cyclohexyl ethers of l7or-[2'-v furyl] -3,5 10 ,7-estratetraene-3, 17-diol.

Similarly the 3-methyl, 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl and 3-cyclohexyl ethers of equilenin, described in Example 1, yield the 3- methyl, 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.- butyl, 3-cyclopentyl and 3-cyclohexyl ethers of 17a-[2'- fur-yl] 1,3,5 ,6,8 (9 -estrapentaene-3, 17-diol.

EXAMPLE 4 A solution of furan (17.8 g.), dry ether (356 ml.) and an ethereal solution of n-butyllithium 1.49 N (168 ml.) is stirred at room temperature for one hour. A solution of estrone S-tetrahydropyranyl ether (17.8 g.) in toluene (700 ml.) is added and the reaction mixture is stirred at room temperature for 16 hours. The product is isolated as indicated in Example 2 to yield the 3-tetrahydropyranyl ether of 17a-[2'-fury1]-1,3,5(10)-estratriene-3,17-diol.

In a similar manner the 3-tetrahydropyranyl ethers of equilin and equilenin are treated with 2-furyllithium to give the corresponding 3-tetrahydropyranyl ethers of 17a- [2-furyl] -1.,3,5 10) ,7-estratetraene-3,17-diol and 17 oz- [2'- furyl] -1,3,5,6,8 (9)-estrapentaene-3,17-diol.

EXAMPLE 5 A solution of the 3-tetrahydropyranyl etherof 17a-[2'- furyl]-1,3,5(l0)-estratriene-3,17-diol, described in EX- ample 4 (21.3 g.) methanol (850 ml.) and a 0.1 N solution of hydrochloric acid (213 ml.) is stirred at room temperature for one hour. Water (850 ml.) is added and the mixture is stirred for 2 hours. The resulting solid is filtered, washed with water and dried. Crystallization from ether-hexane yields 17a- [2'-furyl] -1,3,5 10) -estratriene- 3,17-diol M.P. 153-155.

In a similar manner the 3-tetrahydropyranyl ethers of 1711- [2'-furyl] -1,3,5 (10) ,7-estratetraene-3,17-diol and 17a- [2-furyl]-1,3,5,6,8(9)-estrapentaene-3,l7-diol are hydrolyzed with dilute hydrochloric acid in methanol yielding respectively 17 oc- [2-furyl] -1,3,5 (10) ,7-estratetraene-3,17- diol and 17a-[2'-furyl]-1,3,5,6,8(9) estrapentaene-3,l7- diol.

EXAMPLE 6 A solution of 17a-[2'-furyl]-1,3,5(10)-estratriene-3,17- diol (375 mg.) prepared in Example 5, Pyridine (3.75 ml.) and acetic anhydride (3.75 ml.) is stirred for 16 hours at room temperature. The mixture is poured in ice water and is extracted with ether. The ether is washed with dilute sulfuric acid, bicarbonate and water. After drying and evaporating the solvent to dryness, the 3-acetate of 17a-[2'-furyl]-1,3,5(10)-estratriene-3,17-diol is obtained.

In a similar manner acetylation of 17a-[2-furyl]-1,3, 5 (),7-estratetraene-3,17-diol and 17a-[2-furyl]-1,3,5, 6,8(9)-estrapentaene-3,17-diol yields the corresponding 3- acetates of 17w[2'-furyl]-1,3,5(10),7-estratetraene-3,17- diol and 17u-[2'-furyl]-1,3,5,6,8(9)-estrapentaene-3,l7- diol.

Similarly acylation of 17ot-[2'-furyl]-1,3,5(10)-estratriene-3,17-diol, 17w[2-furyl]-1,3,5(10),7 estratetraene- 3,17-diol and 17u-[2-furyl]-1,3,5,6,8(9) estrapentaene- 3,17-diol with the appropriate acid anhydrides or acid halides yields the corresponding 3-acylates such as the 3- propanoates, 3-butanoates, S-pentanoates, 3-hexanoates and 3-hcptanoates, of 17u-[2'-furyl]-1,3,5 (10)-estratriene- 3,17-diol, 17a-[2-furyl]-1,3,5(10),7 estratetraene-3,l7- diol and 17a-[2'-furyl]-1,3,5,6,8(9) estrapentaene-3,17- diol, respectively.

EXAMPLE 7 m-Chloroperbenzoic acid (4.05 g.) is added by portions, over a period of minutes to a stirred, ice-cold, solution of equilin 3-methyl ether (5 g.) in chloroform (125 ml.). The mixture is stirred for an additional 2 hours in the icebath and then for 30 minutes at room temperature. The solution is washed with a 5% sodium carbonate solution and with water, dried and evaporated. The colour is removed from the crude crystalline product by filtration on a column of alumina. The fractions eluted with 1:1 benzene petroleum ether are combined and crystallized from methanol to yield the 3-methyl ether of 7a,8-epoxyestrone M.P. 176-178 C.

By a similar procedure the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl and 3-cyclohexyl ethers of equilin are oxidized to the corresponding 7a,8-epoxy derivatives with m-chloroperbenzoic acid in chloroform solutions. In this manner, there are obtained the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl and 3-cyclohexyl ethers of 7a,8-epoxyestrone.

EXAMPLE 8 m-Chloroperbenzoic acid (25.8 g.) is added by portions to a stirred, ice-cold suspension of equilin (25.0 g.), in chloroform (500 ml.). After 3 hours, the solution is washed four times with a 5% sodium carbonate solution and with water, dried and evaporated.

The dark red oil, dissolved in benzene (750 ml.), is stirred under nitrogen for 3 hours with dihydropyran (30 ml.), and p-toluenesulfonic acid (500 mg.). Pyridine (0.5 ml.) is added and the solution is washed with water, dried and evaporated. The crude product is chromatographed on Florisil. Elution with mixtures of benzene and ether yields the 3-tetrahydropyranyl ether of 7a,8-epoxyestrone.

EXAMPLE 9 A solution of furan (4.1 g.), ether (82 ml.), and a 1.52 N ethereal solution of n-butyllithium (37.2 ml.) is stirred at room temperature for one hour. Then a solution of the 3-methy1 ether of 7a,8-epoxyestrone (4.1 g.), obtained in Example 7, in toluene (164 ml.), is added and the mixture is stirred at room temperature for 16 hours. Ether and water are added. The organic phase is further washed with water, dried and evaporated to dryness, leaving a solid which upon crystallization from methylene chloride ether yields the 3-methyl ether of 701,8- epoxy-170t-[2'-furyl]-1,3,5(l0)-estratriene-3,17-diol M.P. 188190.

Similarly the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl, 3-cyclohexyl and 3-tetrahydropyranyl ethers of 7u,8-epoxyestrone are transformed when treated with 2-furyllithium to the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl-3-cyclohexyl and 3-tetrahydropyranyl ethers of 7a,8-epoxy-17ot-[2- furyl]-1,3,5( 10 -estratriene-3, 17-diol.

8 EXAMPLE 10 By a similar method to the one described in Example 5, the 3-tetrahydropyranyl ether of 7a,8-epoxy-17a-[2'- furyl]-1,3,5(10)-estratriene-3,17-diol prepared in Example 9, is hydrolyzed with dilute hydrochloric acid in methanol yielding 7a,8-epoxy-17a-[2-furyl]-1,3,5 (l0)-estratriene-3,17-diol.

EXAMPLE 11 Acylation by the method of Example 6 of 70:,8-6POXY- 17a-[2'-furyl]-1,3,5(10)-estratriene-3,17- liol, prepared in Example 10, yields the corresponding 3-acylates such as for example the S-acetate, 3-propanoate, 3-butanoate, 3-pentanoate, 3-hexanoate and 3-heptanoate of 701,8- epoxy-17a-[2'-furyl]-1,3,5(10)-estratriene-3,17-diol.

EXAMPLE 12 A mixture of the 3-methyl ether of l7a-[2-furyl]- 1,3,5(10)-estratriene-3,17-diol (3.2 g.), described in Example 2, a 48% (M/V) solution of peracetic acid (3.2 ml.), sodium acetate (3.2 g.) and chloroform (32 ml.) is stirred at room temperature for 3 hours. The organic solution is washed with water and with a 50% solution of potassium iodide, until no iodine is formed. The solution is further washed with a solution of sodium thiosulfate and then water, dried and evaporated. The residue is crystallized from nitro methane to yield the 3-methyl ether of 3,24-dihydroxy-175,24-epoxy 19,21 dinorchola 1,3, 5(10),22-tetraen-20-one as a mixture of isomers A and B M.P. 191-192 C.

Alternatively m-chloroperbenzoic acid (2.45 g.) is added to a solution of the 3-methyl ether of 17u-[2- furyl]-1,3,5(10)-estratriene-3,l7-diol (2 g.) in chloroform (20 ml.). The mixture is stirred for 30 minutes at room temperature. Ether is added and the solution is washed with sodium carbonate and water, dried and evaporated to dryness, yielding the 3-methyl ether of 3,24-dihydroxy- 17/3,24-epoXy-19,21-dinorchola-1,3,5(10),22 tetraen 20- one as a mixture of isomers A and B.

Similarly oxidation as above, of the 3-methyl ether of 17a-[2-furyl] -1,3,5 10 -estratriene-3,17-diol with m-chloroperbenzoic acid but replacing chloroform with acetone, ether, dioxan, tetrahydrofuran, methanol, benzene, ethyl acetate and acetic acid and for periods of time ranging from 30 minutes to 20 hours affords the 3-methyl ether of 3,24-dihydroxy 176,24 epoxy-19,21-dinorchola-1,3, 5 (10),22-tetraen-20-one as a mixture of isomers A and B.

Again alternatively a mixture of the 3-methyl ether of 17a-[2'-furyl]-l,3,5 (10)-estratriene-3,17-diol (1 g.), chloroform (50 ml.) and p-nitroperbenzoic acid (640 mg.) is stirred at room temperature for one hour. The solid is filtered and the filtrate is washed with sodium bicarbonate and water. After drying and evaporating the solvent, there is obtained a mixture of isomers A and B of the 3-methyl ether of 3,24-dihydroxy-17 3,24-epoxy-19,2l-dinorchola- 1,3,5 10) ,22-tetraen-20-one.

EXAMPLE 13 N-bromosuccinimide (1.08 g.) is added by portions to a suspension of the 3-methyl ether of 17a-[2'-furyl]- 1,3,5(10)-estratriene-3,17-diol (2.16 g.) prepared in Example 2, in methanol (216 ml.) and water (21 ml.). The mixture is stirred for five minutes. Water is added; the mixture is extracted with ether and the ether solution is washed with water, dried and evaporated. The residue is chromatographed on silica gel and the fractions eluted with mixtures of ether and benzene 1:19 and 1:9 are combined and crystallized from methylene chloride-ether to yield the 3-rnethyl ether of 3,24-dihydroxy-1713,24 epoxy- 19,21-dinorchola-1,3,5 l 0) ,22-tetraen-20-one M.P. 184 as a mixture of isomers A and B.

In a similar manner, but replacing methanol by acetone dioxan, ether, tetrahydrofuran, benzene, ethyl acetate or acetic acid, the 3-methyl ether of 17ot-[2'-furyl]-1,3, 5(l0)-estratriene-3,17-diol is oxidized with N-bromosuccinimide in presence of water for approximately 30 minutes at room temperature to afford the 3-methyl ether of 3,24 dihydroxy 17fi,24 epoxy 19,21 dinorchola-1,3, (),22-tetraen-20-one, as mixtures of isomers A and B.

EXAMPLE 14 A mixture of the 3 tetrahydropyranyl ether of 17a-[2'- furyl]-1,3,5(10)-estratriene-3,17-diol (114 g.), obtained in Example 4, chloroform (1140 ml.), sodium acetate (114 g.) and 40% solution of peracetic acid (114 ml.) is stirred at room temperature for 3 /2 hours. The solution is washed with water and sodium bicarbonate, dried and evaporated to dryness. The residue is crystallized from methanol (containing a trace of pyridine) to yield the S-tetrahydropyranyl ether of 3,24-dihydroxy-17p,24- epoxy-19,21-dinorchola-1,3,5(10),22-tetraen-2-0-one as a mixture of isomers A and B.

In a similar manner the 3-tetrahydropyranyl ethers of 17u-[2-furyl]-1,3,5,6,8(9) estrapentaene-3,17-diol, obtained in Example 5 and 7u,8-epoxy-17u-[2'-furyl]-1,3,5- (10)-estratriene-3,17 diol, obtained in Example 9 are oxidized to. yield the 3-tetrahydropyranyl ethers of 3,24- dihydroxy-17/3,24-epoxy 19,21-dinorchola-1,3,5,6,8(9),- 22-hexaene-20-one and 7a,8-17fi,24-diepoxy-3,24 dihydroxy-19,21-dinorchola-1,3,5 10) -22-tetraene-20-one respectively as mixtures of isomers A and B.

EXAMPLE A mixture of the B-tetrahydropyranyl ether of 3,24-dihydroxy-17 3,24 epoxy 19,21-dinorchola-1,3,5(10),22- tetraen-ZO-one (mixtures of isomers A and B) (35 g.), obtained in Example 14, methanol (1400 ml.) and a 0.1 N solution of hydrochloric acid (350 ml.) is stirred at room temperature for 2 hours. The methanol is evaporated under reduced pressure and the resulting solid is filtered yielding a mixture of isomers A and B of 3,24-dihydroxy- 17,3,24-epoxy-19,21 dinorchola-1,3,5(10),22-tetraen-20 one M.P. 234-235 (dec.).

In a similar manner the S-tetrahydropyranyl ethers of 3,24-dihydroxy-17fi,24-epoxy 19,21-dinorchola-1,3,5,6,8- (9), 22-hexaen-20-one and 7a,8-17B,24-diepoxy-3,24-dihydroxy-19,21-dinorchola-1,3,5 (10),22-tetraen-20 one, obtained in Example 14, are hydrolyzed with mild acid to yield mixtures of isomers A and B of 3,24-dihydroxy- 17,9,24-epoxy-19,21-dinorchola 1,3,5,6,8(9),22-hexaen- -one and 7oz,8-17 3,24 diepoxy-3,24-dihydroxy-19,21- dinorchola-3,5 (10)-22-tetraen-20-one, respectively.

EXAMPLE 16 To a solution of the 3-cyclopentyl ether of 17a-[2- fury1]1,3,5 (10)-estratriene-3,l7-diol (55 g.), prepared in Example 2, in chloroform (700 ml.) is added over a pe riod of 15 minutes a solution of m-chloroperbenzoic acid (40.0 g.) in chloroform (50 ml.). The solution is stirred at room temperature for 2 hours. The solution is washed with sodium bicarbonate, water and dried and evaporated. The residue is chromatographed on silica gel. The fractions eluted with benzene-ethyl acetate (19.5 20.5) are combined and crystallized from acetone-hexane yielding the 3-cyclopentyl ether of 3,24-dihydroxy-17,8,24-epoxy- 19,21-dinorchola-1,3,5(10),22-tetraen-20 one, as a mixture of isomers A and B M.P. 173174.

Similarly, oxidation of the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclohexy1 ethers of 170:- [2'-furyl]-1,3,5(10)-estratriene-3,17 diol, described in Example 2, affords the 3-ethyl, 3-propyl, 3-isopropyl, 3- n-butyl, 3-sec.-butyl and 3-cyclohexyl ethers of 3,24-dihydroxy-17,B,24-epoxy 19,21 dinorchola 1,3,5 (10),22- tetraen-ZO-one as mixtures of isomers A and B.

Similarly, the 3-methyl, 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl 3 cyclohexyl and 3-cyclopentyl ethers of 17a-[2'-furyl]-1,3,5,6,8(9)-estrapentaene-3-17- diol, prepared in Example 3 are oxidized to yield the 3- methyl, 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.- butyl, 3-cyclopenty1 and 3-cyclohexyl ethers of 3,24-dihydroxy-17;9,24-epoxy-l9,21 dinorchola 1,3,5,6,8 (9),22-

hexaen-ZO-one. All these compounds are obtained as mixtures of isomers A and B.

EXAMPLE 17 A mixture of the 3-methyl ether of 7a,8-epoxy-17a-[2'- furyl]-l,3,5 10)-estratriene-3,17-diol (53.5 g.), prepared in Example 9, chloroform (53.5 ml.), sodium acetate (53.5 g.) and a 40% solution of peracetic acid (53.5 ml.) is stirred at room temperature for 6% hours. The solution is washed with Water and then with a 50% solution of potassium iodide until no iodine is developed. The solution is further washed with sodium thiosulfate and water, dried and evaporated. The residue is chromatographed on silica gel. The fractions eluted with mixtures of benzene-ethyl acetate 9:1 and 4:1 are combined to yield the 3-methyl ether of 7a,8-17/3,24-diepoxy-3,24-dihydroxy-19,21-dinorchola-1,3,5(10), 22-tetraen-20-one as mixture of isomers A and B. The pure isomer A is obtained by crystallizing the mixture with acetone-hexane M.P. 183-184.

In a similar manner the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl and 3 cyclohexyl ethers of 7a,8-epoxy-17a- [2-furyl] -1,3,5 (10) -estratriene- 3,17-diol, described in Example 9, are oxidized to yield the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 7u,8 175,24-diepoxy-3,24-dihydroxy-19,21 dinorchola 1,3,5 (10),22- tetraen-ZO-one. These compounds are all obtained as mixtures of isomers A and B.

EXAMPLE 18 A mixture of the 3-methyl ether of 17a-['2-fury1]- 1,3,5(10),7-tetraene 3,17-diol (1.65 g.) obtained in Example 3, chloroform (33 ml.), sodium acetate (1.65 g.) and a 40% solution of peracetic acid (3.3 ml.) is stirred at room temperature for five hours, while keeping the temperature between 0 and 5. The reaction is worked up as previously and the crude residue is crystallized from acetone-hexane yielding the 3-methyl ether of 7a,8-17B,- 24-diepoxy-3,24-dihydroxy-19,21 dinorchola-1,3,5 10) 22-tetraen-20 one M.P. l8l C., as a mixture of isomers A and B.

In a similar manner oxidation of the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 17a [2-furyl]-1,3,5(10),7-estratetraene-3,17-diol, obtained in Example 3, affords the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3 sec-butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 7a,8-17;8,24-diepoxy-3,24- dihydroxy-19,2l-dinorchola-1,3,5(10),22 tetraen 20- one. All these compounds are obtained as mixtures of isomers A and B.

By a similar procedure 17a-[2'-furyl]-l,3,5(10),7-estratetraene-3,17-diol and its S-tetrahydropyranyl ether, re spectively prepared in Examples 4 and 5 are oxidized to yield 7a,8-17B,24-diepoxy-3,24 dihydroxy-19,21-dinorchola-1,3,5(10),22-tetraen-20-one and its 3 tetrahydropyranyl ether, respectively, as mixtures of isomers A and B.-

Similarly oxidation of the 3-acetate, 3-propanoate, 3- butanoate, 3-pentanoate, 3-hexanoate and 3-heptanoate of 17a-[2'-furyl]-1,3,5(10),7 estratetraene 3,17-diol yields the 3-acetate, 3-propanoate, 3-butanoate, 3-pentanoate, 3-hexanoate and 3-heptanoate of 70,8 17fi,24-di epoxy-3,24 dihydroxy l9,21-dinorchola-1,3,5(10),22- tetraen-ZO-one, as mixtures of isomers A and B.

EXAMPLE 19 By the procedure described in Example 12, 17a[2- furyl]-l,3,5(l0) estratriene-3,17-diol, 17a[2-furyl]-l,3, 5,6,8(9)-estrapentaene3-,17-diol and 7a,8-epoxy-17a-[2'- furyl]-1,3,5( l0) estratriene 3,17 diol, respectively described in Example 5 and 10 are oxidized to give mixtures of isomers A and B of 3,24-dihydroxy-175,24-0poxyl9,21-dinorchola-l,3,5(10),22-tetraen-20-one, 3,24 dihydroxy-1718,24 epoxy-19,21 dinorchola 1,3,5,6,8(9),22-

hexaen-ZO-one and 7a,8-1713,24-diepoxy-3,24 dihydroxy- 19,2 l-dinorchola- 1,3,5 ()-22-tetraen-20-one.

Similarly the 3-acetates, 3-propanoates, 3-butanoates, 3- pentanoates, 3-hexanoates and 3-heptanoates of 17a-[2'- furyl]-1,3,5(10)-estratriene-3,17-diol, 17a-[2'-furyl]-1,3, 5,6,8(9)-estpentaene 3,17-diol and 7a,8-epoxy-l7a[2- furyl]-1,3,5(10) estratriene 3,17-diol respectively described in Example 6 and 11, are transformed by oxidation to the 3-acetates, 3-propanoates, 3-butanoates, 3- pentanoates, 3-hexanoates and 3-heptanoates of 3,24-dihydroxy-17fl,24-ep0xy19,21 dinorchola 1,3,5(10),22- tetraen-ZO-one, 3,24 dihydroxy-17B,24-epoxy-19,21-dinorchola-1,3,5,6,8(9),22-hexaen 20 one and 7u,8-17fi, 24-diepoxy-3,24-dihydroxy 19,21-dinorchola-1,3,5(10), 22-tetraen-20-one, respectively. All these compounds are obtained as mixtures of isomers A and B.

EXAMPLE 20 To a solution of the mixtures of isomers A and B of the 3 tetrahydropyranyl ether of 3,24 dihydroxy 1713,24- epoxy-19,21-dinorchola-1,3,5(10),22 tetraen-ZO-one (62 g.), described in Example 14, in acetone (2500 ml.) is added at 10 a 8 N chromic acid solution (81 ml.). After stirring for 20 minutes at 10 the excess oxidant is destroyed by the addition of isopropanol. Water is added and most of the solvent is evaporated under reduced pressure. The resulting solid is filtered, washed with water and dried. This solid is purified by chromatography on silica gel. The fractions eluted with mixtures of benzene-ethyl acetate (19:1 and 9:1) are combined yielding 3,17,3-dihydroxy- 20-oxo-19,21-dinorchola 1,3,5(10),22 tetraenoic and 6- lactone M.P. 278-280 C.

In a similar manner oxidation of the mixtures of isomers A and B of the 3-tetrahydropyranyl ethers of 3,24-dihydroxy-17,3,24-epoxy 19,21 dinorchola 1,3,5,6,8(9),22- hexaen-ZO-one and 7a,8-17;3,24-diepoxy 3,24 dihydroxy- 19,21-dinorchola-1,3,5(10),22 tetraen 20 one yields respectively 3,17fl-dihydroxy-20-oxo-19,21-dinorchola-1,3,5, 6,8(9),22-hexaenoic acid e-lactone and 3,17/3-dihydroxy- 7a,8-epoxy-20-oxo-19,2 l-dinorchola 1,3,5(10),22 tetraenoic acid fi-lactone.

EXAMPLE 21 To a solution of the mixture of isomers A and B of the 3-methyl ether of 3,24-dihydroxy 175,24-epoxy 19,21- dinorchola-1,3,5(10),22-tetraen-20-one (20 g.) obtained in Example 12, in purified acetone (1000 ml.) is added a 8 N chromic acid solution (26.4 ml.). The temperature of the solution is kept at 10 during the addition of the oxidant. After stirring for an additional 10 minutes, isopropanol is added, followed by water. The acetone is exaporated and the solid residue is filtered, washed with water and dried. This solid is crystallized from methylene chloride methanol, yielding the 3-methyl ether of 3,175- dihydroxy-ZO-oxo-19,21-dinorchola-l,3,5(10) 22 tetraenoic acid B-lactone M.P. 206207 C.

In a similar manner the mixtures of isomers A and B of the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl and 3-cyclohexyl ethers of 3,24-dihydroxy-17,8,24-epoxy- 19,21-dinorchola-1,5(10),22-tetraen-20-one, described in Example 16, are oxidized to yield respectively the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl and 3-cycl0- hexyl ethers of 3,17/8-dihydroxy-20-oxo-19,2l-dinorchola- 1,3,5(10),22-tetraenoic acid B-lactone.

Similarly the mixtures of isomers A and B of the 3- methyl, 3 ethyl, 3 propyl, 3 isopropyl, 3 n-butyl, 3-sec.-butyl, 3-cyclopentyl and 3-cyclohexyl ethers of 3,24- dihydroxy-l7B,24-epoxy-19,21 dinorchola 1,3,5,6,8(9), 22-haxaen-20-one are oxidized to yield respectively the 3- methyl, 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.- butyl, 3-cyclopentyl and 3-cyclohexyl ethers of 3,17,8-dihydroxy-20-oxo-19,21-dinorchola-1,3,5,6,8 (9),22 hexaenoic acid fi-lactone, respectively.

12 EXAMPLE 22 To a solution of the mixtures of isomers A and B Of the 3-cyclopentyl ether of 3,24-dihydroxy-l7,3,24-epoxy- 19,21-dinorchola-1,3,5(10),22-tetraen 20 one (4.25 g.). described in Example 16, in acetone (210 ml.) is added at 10 a 8 N chromic acid solution (5.6 ml.). The mixture is stirred for 10 minutes, then the excess oxidant is decomposed by the addition of isopropanol. The acetone is evaporated and the residue is diluted with water. The resulting solid is filtered, washed with water and dried. Crystallization of this solid from methylene chloridemethanol affords the 3-cyclopentyl ether of 3,17p-dihydroxy-20-oxo-19,2l-dinorchola 1,3,5(10),22 tetraenoic acid d-lactone M.P. 230-232".

EXAMPLE 23 A solution of 3,17/3-dihydroxy-20-oxo-19,21-dinorchola- 1,3,5(10),22-tetraenoic acid 6-lactone (8.5 g.) described in Example 30, pyridine ml.) and acetic anhydride (85 ml.) is stirred at room temperature for 30 minutes. The solution is poured into ice-water and the resulting solid is filtered, washed with Water and dried. The solid is chromatographed on silica gel. The fractions eluted with benzene-ethyl acetate (19:1) are combined and crystallized from acetone-hexane yielding the 3-acetate of 3,175- dihydroxy-20-oxo-19,21 dinorchola 1,3,5(10),22 tetraenoic acid fi-lactone M.P. 191192 C.

In a similar manner but replacing acetic anhydride by other acylating agents, 3,17,8-dihydroxy 20-oxo-19,21- dinorchola-1,3,5(10),22-tetraenoic acid fi-lactone is esterilied to yield the 3-propanoate, 3-butanoate, 3-petanoate, 3-hexanoate and 3-heptanoate of 3,17p-dihydroxy-20-oxo- 19,21-dinorchola-1,3,5(10),22-tetraenoic acid e-lactone.

By a similar procedure acylation of 3,17fi-dihydroxy- 20-oxo-19,2l-din0rchola-l,3,5,6,8(9),22 hexaenoic acid acid and 3,17B-dihydroxy-7a,8-epoxy-20-oxo-19,21- dinorchola-1,3,5(10),22-tetraenoic acid B-lactone, described in Example 30, affords, the corresponding 3-acylates such as for example the S-acetates, 3-propionates, 3,butanoates, 3- pentanoates, 3-hexanoates, 3-heptanoates, of 3,175-dihydroxy-20-oxo-19,21 dinorchola-1,3,5,6,8 (9),22-hexaenoic acid 6-lactone and 3,17/3-dihydroxy-7a,8-epoxy-20- oxo-19,21 dinorchola 1,3,5(10),22 tetraenoic acid e-lactone.

EXAMPLE 24 To a solution of the mixture of isomers A and B of the 3-methyl ether of 7a,8-17,B,24-diepoxy-3,24-dihydroxy 19,21 dinorchola 1,3,5(10),22-tetraen 20- one (22.1 g.), described in Example 17, in acetone (490 ml.) is added at 10 a 8 N chromic acid solution (28.5 ml.). After stirring for an additional 30 minutes, the excess oxidant is destroyed with isopropanol. Water is added and the solvent is evaporated under reduced pressure. The resulting solid is filtered, washed with water and dried. This solid is chromatographed on silica gel. The fractions eluted with a mixture of 19:1 benzeneethyl acetate are combined and crystallized from methyene chloride-methanol yielding the B-methyl ether of 3,1713 dihydroxy 7a,8 epoxy-20-oxo-19,21-dinorchola- 1,3,5(10),22-tetraenoic acid e-lactone M.P. 227-230.

In a similar manner, oxidation of the mixtures of isomers of the 3-ethyl, 3-propyl, 3-isopropyl, S-n-butyl, 3- sec.-butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 701,8- 17;8,24-diepoxy-3,24 dihydroxy 19,21 dinorchola- 1,3,5 l0) ,22-tetraen-20-one yields the corresponding ketolactones such as the 3-ethyl, 3-propyl, 3-isopropyl, 3-nbutyl, 3-sec.-butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 3,175 dihydroxy 7a,8-epoxy-20-oxo-19,21-dinorchola- 1,3,5 10) ,22-tetraenoic acid fi-lactone.

EXAMPLE 25 By a procedure similar to the one described by A. D. Cross et al. in Steroids, vol. 4, page 423 (1964), 3,1713- dihydroxy 20 OX0 19,21 dinorchola 1,3,5(10),22-

tetraenoic acid fi-lactone, 3-175-dihydroxy-20-oxo-19,21- dinorchola-1,3,5,-6,8(9),22-hexaenoic acid a-lactone and 3,175 dihydroxy 7oc,8 epoxy 20 oxo-19,21-dinorchola 1,3,5 (10),22 tetraenoic acid 6-lactone, described in Example 30, are treated with dihydropyran in benzene solutions and in presence of p-toluenesulfonic acid to yield the corresponding 3-tetrahydropyranyl ethers of 3,175 dihydroxy 20 oxo -19,21-dinorchola- 1,3,5 (10),22 tetraenoic acid B-lactone, 3,175-dihydroxy- 20-oxo-19,21-dinorchola-1,3,5,6, 8(9),22 hexaenoic acid eS-lactone and 3,175 dihydroxy 7a,8 epoxy 20 oxo- 19,21-dinorchola-1,3,5(10),22-tetraenoic acid a-lactone.

EXAMPLE 26 To a suspension of prehydrogenated 10% palladium on calcium carbonate (625 mg.) in a little dioxan is added a solution of the mixture of isomers A and B of the 3-methyl ether of 3,24-dihydroxy 175,24-epoxy- 19,21 dinorchola 1,3,5 (10),22-tetraen-20-one (2.5 g.), described in Example 12, in dioxan (100 ml.). The mixture is hydrogenated for 35 minutes at room temperature and at normal pressure. The catalyst is filtered and washed with dioxan. The filtrate is evaporated to dryness. The residue is purified by precipitation from acetonehexane yielding amorphous 3-methyl ether of 3,24-dihydroxy 175,24 epoxy 19,21 dinorchola 1,3,5(10)- trien-ZO-one, as a mixture of isomers A and B.

Similarly, hydrogenation of the mixtures of isomers A and B of the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl and 3-cyclohexyl ethers of 3,24- dihydroxy-175,24-epoXy-1'9,21 dinorchola 1,3,5 (10),22- tetraen-20-one, prepared in Example 16, afiords the 3- ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3- cyclopentyl, 3 cyclohexyl ethers of 3,24-dihydroxy- 175,24-epoxy-19,2l-dinorchola 1,35(10) trien 20- one, as mixtures of isomers A and B.

In a similar manner the mixture of isomers A and B of 3-methyl, 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3- sec.-butyl, 3-cyclopentyl, 3-cyclohexy1 ethers of 3,24-dihydroxy 175,24 epoxy 19,21-dinorchola-1,3,5,6,8 (9),22-hexaen-20-one, obtained in Example 16, are hydrogenated to yield the B-methyl, 3-ethyl, 3-propyl, 3- isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 3,24 dihydroxy 175,24 epoxy 19,21- dinorchola 1,3,5,6,8(9) pentaen 20 one, as mixtures of isomers A and B.

By a similar procedure, hydrogenation of the mixtures of isomers A and B of the 3-methyl, 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-sec.-butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 7w,8-175,Q,4+liepoxy 3,24 dihydroxy 19,21 dinorchola l,3,5(10),22- tetraen-ZO-one, obtained in Example 17, affords the 3- methyl, 3-ethy1, 3-propyl, 3-isopropyl, B-n-butyl, 3-sec.- butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 7a,8l7[3,24- diepoxy 3,24 dihdroxy 19,21 dinorchola 1,3,5(10)- triene20-one, as mixtures of isomers A and B.

Similarly hydrogenation of the mixtures of isomers A and B of the B-tetrahydropyranyl ethers of 3,24-dihydroxy 175,24 epoxy 19,21 dinorchola 1,3,5(10), 22. tetraen 2-0 one, 3,24 h dihydroxy-175,24-epoxy- 19,21 dinorchola 1,3,5,6,8(9),22-hexaen-20-one and 7a,8-175,24 diepoxy 3,24 dihydroxy 19,21-dinorchola 1,3,5(10),22 tetraen 20 one, described in Example 14, yields the 3-tetrahydropyranyl ethers of 3,24- dihydroxy 175,24 epoxy 19,21 dinorchola 1,3,5 10) trien 20 one, 3,24-dihdroxy-175,24-epoxy-19,21- dinorchola-1,3,5,6,8(9)-pentaen-20-one and 7a,8-175,24- diepoxy 3,24 dihydroxy 19,21 dinorchola 1,3,5(10)- trien-ZO-one, respectively as mixtures of isomers A and B.

In a similar manner the mixtures of isomers A and B. 3,24 dihydroxy 175,24 epoxy 19,21-dinorchola- 1,3,5 (1 ),22 tetraen 20 one, 3,24-dihydroxy-175,24- epoxy 19,21 dinorchola 1,3,5,6,8(9'),22-hexaen-20- one and 7u,8 175,24 diepoxy-3,24-dihydroxy-19,21- dinorchola 1,3,5(10),22 tetraen 20 one, obtained in 14 Example 15, are hydrogenated to yield mixtures of isomers A and B of 3,24-dihydroxy-175,24-epoxy-19,21- dinorchola 1,3,5,(10) trien 20-one, 3,24-dihydroxy- 175,24 epoxy 19,21 dinorchola 1,3,5,6,8(9)- pentaen 20 one and 7a,8 175,24-diepoxy-3,24-dihydroxy-19,21-dinorchola-1,3,5 10) -trien-20-one.

By a similar procedure, hydrogenation of the mixtures of isomers A and B of the 3-acetates, 3-propanoates, 3- butanoates, 3-pentanoates, 3-hexanoates, and S-heptanoates of 3-24-dihydroxy-175,24-epoxy-19,21-dinorchola- 1,3,5 (10),22-tetraen-20-one, 3,24 dihydroxy 175,24 epoxy-19,2l-dinorchola-1,3,5,6,8(9),22-hexaen-20 one and 7a,8-175,24-diepoxy-3,24-dihydroxy 19,21 -n dinorcho1a-1,3,5(10),22-tetraen-20-one, described in Example 19, affords the 3-acetates, 3-propanoates, 3-butanoates, 3- pentanoates, 3-hexanoates and 3-heptanoates of 3,24-dihydroxy-175,24-epoxy-19,2l-dinorchola 1,3,5 (10) trien- 20-one, 3,24-dihydr0xy-175,24 epoxy 19,21-dimorchola- 1,3,5,6,8(9)-pentaen-20-one and 7a,8 175,24 diepoxy- 3,24-dihydroxy 19,21-dinorchola-1,3,5 (10)-trien-20-one. Those compounds are all obtained as mixtures of isomers A and B.

EXAMPLE 27 A mixture of 3,175-dihydroxy-20-oxo-19,2l-dinorchola- 1,3,5 (10),22-tetraenoic acid fi-lactone (15.4 g.), obtained in Example 30, methylene chloride (620 ml.), glacial acetic acid (770 ml.) and zinc dust (77 g.) is stirred for 2 hours at room temperature. The metal is filtered and Washed with methylene chloride. The filtrate is evaporated under reduced pressure to a small volume and Water is added. The resulting solid is filtered, washed with water and dried. This solid is crystallized from acetone yielding 3,175-dihydroxy-20-oxo-19,21 dinorchola l,3,5(10)-trienoic acid ot-lactone M.P. 288290.

Similarly reduction of 3,175-dihydroxy-20-oxo-19,21- dinorchola-l,3,5,6,8(9),22-hexaenoic acid 6-lactone and 3,175-dihydroxy-7a,8-epoxy-20-oxo 19,21 dinorchola- 1,3,5 (l0),22-tetraenoic acid fi-lactone, affords 3-l75-dihydroxy-20-oxo-19,21-dinorchola 1,3,5,6,8(9) pentaenoic acid B-lactone and 3,175-dihydroxy-7a,8-epoxy-20 oxo- 19,21-dinorchola-1,3,5 (10)-trienoic fi-lactone, respectively.

EXAMPLE 28 A mixture of the S-methyl ether of 3,l75-dihydroxy-20 oxo-19,21-dinorchola-1,3,5 (l0),22-tetraenoic acid B-lactone (350 mg.), obtained in Example 31, chloroform (10.5 ml.), glacial acetic acid (35 ml.) and zinc dust (1.75 g.), is stirred at room temperature for 30 minutes. The metal is filtered. The filtrate is diluted with chloroform. The chloroform solution is washed with water and sodium bicarbonate and again water to neutrality. After drying and evaporating the solution, the residue is crystallized from methylene chloride-methanol yielding the 3- methyl ether of 3,175-dihydroxy-20-oxo-19,21-dinorcholal,3,5(10)-trienoic acid 8-lactone M.P. 167.

In a similar manner the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 3 ,l75-dihydroxy-20-oxo-19,21-dinorchola-1,3,5,(10),22- tetraenoic acid fi-lactone, obtained in Examples 31 and 32, are reduced to yield the 3-ethyl, 3-propyl, 3-isopropyl, 3-nbutyl, 3-sec.-butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 3,175-dihydroxy-20-oxo 19,21 dinorchola 1,3,5(10) trienoic acid B-lactone.

Similarly the 3-methyl, 3-propyl, 3-ethel, 3-isopropyl, 3-n-butyl, 3-cyclopentyl, 3-cyclohexy1 ethers of 3,175- dihydroxy-20-oXo-19,21 dinorchola 1,3,5,6,8(9),22 hexaenoic acid B-lactone are reduced to afford the 3- methyl, 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.- butyl, 3-cyclopentyl, 3-cyclohexy1 ethers of 3,175-dihydroxy-ZO-oxo-19,21-dinorchola 1,3,5,6,8(9) pentaenoic acid fi-lactone.

In a similar manner reduction of the 3-tetrahydr0pyranyl ethers of 3,175-dihydroxy-20-oxo-19,2l-dinorchola- 1,3,5 (10),22-tetraenoic acid fi-lactone, 3-175-dihydroxy- 15 20-oxo-19,21-dinorchola-1,3,5,6,8(9),22 hexaenoic acid 6-lactone and 3,175-dihydroxy-7u,8-epoxy-20-0xo-19,21- dinorchola-1,3,5(10),22-tetraenoic acid fi-lacetone, yields the 3-tetrahydropyranyl ethers of 3,175-dihydroxy-20-oxo- 19,21-dinorchola-1,3,5(10)-trienoic acid fi-lactone, 3,175- dihydroxy-20-oxo-19,2 1-dinorchola-1,3,5,6,8 (9 pentaenoic acid 6-lactone and 3,175-dihydroxy-7a,8-epoxy-20- oxo-19,21-dinorchola-1,3,5(10)-trienoic acid B-lactone.

EXAMPLE 29 A mixture of the 3-methyl ether of 3,175-dihydroxy- 7u,8-epoxy-20-oxo-19,21-dinorchola-1,3,5(10),22 tetraenoic acid 6-lactone (9.2 g.), described in Example 34, chloroform (275 ml.), glacial acetic acid (370 ml.) and zinc dust (46 g.) is stirred for 60 minutes at room temperature. The metal is filtered and washed with chloroform. The filtrate is evaporated to a small volume and the residue is diluted with water. The resulting solid is filtered, washed with water and dried yelding the 3-methyl ether of 3,175-dihydroxy-7a,8-epoxy-20-oxo-19,2l-dinorchola-l,3,5(10)-trienoic acid E-lactone M.P. 214-217".

Similarly the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 3,175- dihydroxy 7a,8 epoxy 20 oxo 19,21 dinorchola- 1,3,5(10),22-tetraenoic acid 6-lactone are reduced to yield the 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl, 3-cyclohexyl ethers of 3,175-dihydroxy- 7a,8-epoxy-20-oxo-19,2l-dinorchola 1,3,5 (10) trienoic acid e-lactone.

EXAMPLE 30 A solution of 3,175-dihydroxy-20-oxo-19,21-dinorchola- 1,3,5(10)-trienoic acid -lactone (7.6 g.), prepared in Example 39, pyridine (76 ml.) and acetic anhydride (76 ml.) is stirred for two hours at room temperature. The solution is poured in ice-Water and the resulting solid is filtered, washed with water and dried. Crystallization of this solid with acetone and then methylene chloridemethanol affords the 3-acetate of 3,175-dihydroxy-20-oxo- 19,21-dinorchola,1,3,5(10)-trienoic acid B-lactone M.P. 212214.

In a similar manner acylation with other acylating agents of 3,175-dihydroxy 20-oxo-19,21-dinorchola-1,3, 5(10)-trienoic acid a-lacetone affords the 3-propanoate, 3-butanoate, 3-pentanoate, 3-hexanoate and 3-heptanoate of 3,175 dihydroxy-ZO-oxo-19,21-dinorchola-1,3,5(10)- trienoic acid B-lactone.

Similarly acylation of 3,175-dihydroxy-20-oxo-19,21- dinorchola-1,3,S,6,8(9)-pentaenoic acid fi-lactone and 3,175-dihydroxy-7a,8-epoxy-20-oxo 19,21 dinorchola- 1,3,5 10)-trienoic acid B-lactone yields the corresponding 3-acylates such as the 3-acetates, 3-propanoates, 3- butanoates, 3-hexanoates, 3-pentanoates and 3-heptanoates of 3,l75-dihydroxy-20-oxo-l9,2l-dinorchola-1,3,5,6,8(9)- pentaenoic acid fi-lactone and 3,175-dihydrxy-7u,8-epoxy- 20-oxo-19,21-dinorchola-1,3,5 10) -trienoic acid fi-lactone.

EXAMPLE 3 1 A mixture of the 3 acetate of 3,175 dihydroxy-20- oxo 19,21 dinorchola 1,3,5 (10),22-tetraenoic acid 6- lactone (1 g.), described in Example 33, glacial acetic acid (50 m1.) and zinc dust g.) is stirred for one hour at room temperature. The metal is filtered and the filtrate is diluted with water. The resulting solid is filtered, washed with water and dried to yield the 3-acetate of 3,175-dihydroxy 20 oxo 19,21-dinorchola-1,3,5()-trienoic acid a-lactone identical with the product obtained in Example 30.

In a similar manner the 3-propanoate, 3-butanoate, 3- pentanoate, 3 hexanoate, 3 heptanoate of 3,175-dihydroxy oxo 19,21-dinorchola-1,3,5(10),22-tetraenoic acid fi-lactone, described in Example 33, are reduced to yield the 3-propanoate, S-butanoate, 3-pentanoate, 3-hexanoate and 3-heptanoate of 3-175-dihydroxy- 20 oxo 19,21 dinorchola-1,3,5(10)-t1ienoic acid 6- lactone.

Similarly reduction of the 3 acetates, 3 propanoates, 3 butanoates, 3 pentanoates, 3 hexanoates and 3-heptanoates of 3,175 dihydroxy 20 oxo-19,21-dinorchola- 1,3,5,6,8(9),22 hexaenoic acid 6 lactone and 3,175-dihydroxy 7a,8 epoxy 20-oxo-19,21-dinorchola-1,3,S (10),22L- tetraenoic acid iS-lactone, obtained in Example 33, affords the 3-acetates, 3-propanoates, 3-butanoates, 3 pentanoates, 3 hexanoates and 3-heptanoates of 3, dihydroxy 20 oxo-19,21-dinorchola-1,3,56,8(9)- pentaenoic acid 5 lactone and 3,175 dihydroxy-704,8- epoxy 20 oxo 19,21-dinorchola-1,3,S(10)-trienoic acid B-lactone.

EXAMPLE 32 By the method described in Example 30, the mixtures of isomers A and B of 3,24-dihydroxy-175,24-ep0xy-19, 21 dinorchola 1,3,5 (10) trien-ZO-one, 3,24-dihydroxy- 175,24 epoxy 19,21 dinorchola-1,3,5,6,8 (9)-pentaen- 2O one and 7u,8 175,24-diepoxy-3,24-dihydroxy-19, 21 dinorchola 1,3,5(10) trien-20-one, obtained in Example 36, are Oxidized with chromic acid in acetone solutions to yield 3,175 dihydroxy 20-oxo-19,21-dinorchola-1,3,5(10)-trienoic acid 6 lactone, 3,175 dihydroxy 20 oxo 19,21-dinorch0la-1,3,5,6,8(9)-pentaenoic acid 6 lactone and 3,17 dihydr0xy-7a,8-epoxy- 20 oxo 19,21 dinorchola-1,3,5(10)-trienoic acid 6- lactone.

Similarly oxidation of mixtures of isomers A and B of the 3-acetates, 3-propanoates, 3-butanoates, 3-pentanoates, 3-hexanoates and 3-heptanoates of 3,24 dihydroxy 175, 24 epoxy 19,21 dinorchola-1,3,5(10)-trien-20-one, 3,24 dihydroxy-175,24 epoxy-19,21-dinorchola-1,3,5,6,8 (9) pentaen 20 one and 7a,8-175,24-diepoxy-3,24- dihydroxy 19,21 dinorchola 1,3,5(10)-trien-20-one, obtained in Example 36, yields the 3-acetates, 3-propanoates, 3-butanoates, 3-pentanoates, 3-hexanoates and 3- heptanoates of 3,175 dihydroxy 20 oxo-19,21-dinorchola 1,3,5 10) trienoic acid fi-lactone, 3,175-dihydroxy 20 oxo 19,21 dinorchola-1,3,5,6,8(9)-pentaenoic acid 6 lactone and 3,175-dihydroxy-7u,8-epoxy- 2O oxo 19,21 dinorchola-1,3,5(10)-trienoic acid 6- lactone.

In a similar manner the mixtures of isomers A and B of the 3-methyl, 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3 sec. butyl, 3-cyclopentyl and 3 cyclohexyl ethers of 3,24 dihydroxy 175,24 epoxy-19,21-dinorchola-1,3, 5(10) trien 20 one, 3,24-dihydroxy-175,24-ep0xy- 19,21 dinorchola 1,3,5,6,8(9) pentaen-ZO-one and 7a,8-17}3,24 epoxy 3,24 dihydroxy-19,21 dinorchola 1,3,5 (10) trien 20 -one, obtained in Example 36, are oxidized to afford the 3-methyl, 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopentyl and 3-cyclohexyl ethers of 3,175 dihydroxy 2O oxo-19,21-dinorchola-1,3,5(10)-trienoic acid e-lactone, 3,175-dihydroxy- 20 oxo 19,21 dinorchola-1,3,5,6,8(9)-pentaenoic acid B-lactone and 3,175 dihydroxy 7a,8 ep0xy-20-oxo-19, 2l-dinorchola-1,3,5 (10)-trienoic acid fi-lactone.

EXAMPLE 33 Sodium borohydride (178 mg.) is added by portions to a solution of the 3-methyl ether of 3,175-dihydroxy- 20 oxo 19,21 dinorchola-1,3,5(10)-trienoic acid 5- lactone (3.3 g.), prepared in Examples 28 and 32, in dioxan (82.5 ml.) and water (16.5 ml.). The solution is stirred for 30 minutes at room temperature. Water is added and the mixture is extracted with ether. The ether is washed with water, dried and evaporated to dryness. The residue is crystallized from methylene chloride-ether to yield the 3-methyl ether of 3,175,20 tri hydroxy 19,21-dinorchola 1,3,5 (10) trienoic acid 7 lactone M.P. 208- 210.

In the same manner the 3-ethyl, 3-propyl, 3-isopropyl, 3 n butyl, 3-sec.-butyl, 3-cyclopentyl and 3-cyclohexyl 17 others of 3,175 dihydroxy 2O ox-19,21-dinorchola- 1,3,5(10)-trienoic acid fi-lactone, prepared in Examples 28 and 32, are reduced to yield the 3-ethyl, 3-propyl, 3- isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopen-tyl and 3-cyclohexyl ethers of 3,175,20 trihydroxy 19,21 dinorchola-1,3,5 10) -trienoic acid 'y-lactone.

In the same manner the 3-methyl, 3-ethyl, 3-propyl, 3- isopropyl, 3-n-butyl, 3-sec.-butyl, 3-cyclopenty1 and 3-cyclohexyl ethers of 3,175 dihydroxy 2O oxo-19,21-dinorehola 1,3,5,6,8(9) pentaenoic acid a-lactones, obtained in Examples 28 and 32, are reduced to give the 3- rnethyl, 3-ethyl, 3-propyl, 3-isopropyl, 3-n-butyl, 3-sec.- butyl, 3-cyclopentyl and 3-cyclohexy1 ethers of 3,17,53,20- trihydroxy 19,21 dinorchola 1,3,5,6,8( 9)-pentaenoic acid 'y-lactone.

In a similar manner, reduction of the 3-tetrahydropyranyl ethers of 3,175 dihydroxy 20 oxo-19,21-dinorchola-l,3,5(10) trienoic acid a-lactone, 3,17B-dihydroxy- 20 oxo 19,21 dinorchola-l,3,5,6,8 (9)-pentaenoic acid 'y-lactone and 3,1713 dihydroxy 70;,8 epoxy-20pm- 19,21-dinorchola-l,3,5(10) trienoic acid 5 lactone prepared in Example 28 aifords respectively the 3-tetrahydropyranyl ethers of 3,17,53,20 trihydroxy 19,21 dinorchola 1,3,5-(l0) trienoic acid 74210110116, 3,175,20-tr-ihydroxy 19,21 dinorchola 1,3,5,6,8(9)-pentaenoic acid -lactone and 701,8 epoxy 3,175,20 trihydroxy-19,2ldinorchola-1,3,5 l0) -trienoic acid 'y-lactone.

By a similar procedure reduction with sodium borohydride of 3,1718 dihydroxy 20 oxo-19,21-dinorchola-1, 3,5 trienoic acid a-lactone, 3,17/3 dihydroxy 20- oxo 19,21 dinorchola l,3,5,6,8(9)-pentaenoic acid e-lactone and 3,17 3 d-ihydroxy 7a,8 epoxy-20-oxo-19, 21 dinorchola 1,3,5(l0) trienoic acid 6-lactone prei 3 cyclohexyl ethers of 7a,8 epoxy 3,176,20-trihydroxyl19,21-dinorchola-1,3,-5 (10)- trienoic acid -lactone.

EXAMPLE 34 A solution of 3,l7fl,20-trihydroxy-.19,2l-dinorchola- 1,3,5(10)-trienoic acid y-lactone (7.0 g.) prepared in Example 33 in pyridine (70 ml.) and acetic anhydride (70 ml.) is stirred at room temperature for 60 minutes. The solution is poured in ice-water and the resulting solid is filtered, washed with water and dried. Crystallization of this solid with methylene chloride-methanol affords the 3- acetate of 3,17fl,20trihydroxy-19,21-dinorchola-1,3,5( l0)- trienoic acid 'y-lactone M.P. ZOO-202 C.

Similarly acylation with other acylating agents of 3,176,20 trihydroxy 19,21 dinorchola 1,3,5(l0) trienoic acid 'y-lactone affords the corresponding 3-acylates of 3,175,20 trihydroxy 19,21 dinorchola 1,3,5(10)- trienoic acid y-lactone such as the 3-propanoate, 3-butanoate, 3-pentanoate, 3-hexanoate and 3-heptanoate.

In a similar manner acylation of 3,175,20-trihydroxy- 19,21-dinorchola 1,3,5,6,8(9) pentaenoic acid -lactone and 7a,8-epoxy-3,175,20-trihydroxy-l,3,5(l0)-trienoic acid and -lactone, prepared in Example 33 yields the 3-acetates, 3-propanoates, 3-butanoates, 3-pentanoates, 3-hexanoates, 3-heptanoates of 3,17p,20-trihydroxy-19,2 l-dinorchola-l,3,5(l0)-trienoic acid -lactone and 7a,8-epoxy- 3,l7B,20-trihydroxy-19,21-dinorchola-l,3,5(l0) trienoic acid 'y-lactone.

pared in Example 27 and 32 yields respectively 3,175,20- "trihydroxy-19,21-din0rchola-1,3,5 (10) trienoic acid 7- 18 I claim: 1. A compound selected from those of the formula wherein R is selected from the group which consists of hydrogen, lower alkyl containing from one to four carbon atoms, cycloalkyl containing from five to six carbon atoms, tetrahydropyranyl and acyl groups containing from two to seven carbon atoms.

2. A compound selected from those of the formula wherein R is selected from the group which consists of hydrogen, lower alkyl containing from one to four carbon atoms, cycloalkyl containing from five to six carbon atoms, tetrahydropyranyl and acyl groups containing from two to seven carbon atoms.

3. A compound selected from those of the formula wherein R is selected from the group which consists of hydrogen, lower alkyl containing from one to four carbon atoms, cycloalkyl containing from five to six carbon atoms,

1 9 20 and and wherein R is selected from the group which consists of hydrogen, lower alkyl containing from one to four carbon atoms, cycloalkyl containing from five to six carbon 0 atoms, tetrahydropyranyl and acyl groups containing from two to seven carbon atoms, which comprises subjecting to the action of sodium borohydride in solution in a cyclic ether a compound selected from those of the formulae References Cited UNITED STATES PATENTS 3,413,288 11/1968 Creger 260-23957 ELBERT L. ROBERTS, Primary Examiner 30 US. Cl. X.R. 

